Development of MAO-A and 5-HT_2AR Dual Inhibitors with Improved Antidepressant Activity

Abstract

Designing dual-target inhibitors targeting 5-HT2AR and MAO-A could synergistically promote interstitial 5-HT levels, so as to exhibit a more efficient antidepressant effect. On the premise of maintaining the original pharmacophore binding, arylpiperazine scaffolds and 5-oxygen-substituted oxoisoaporphines were hybridized to afford 15 dual-target inhibitors through suitable linkers. Among all inhibitors, I 14 exhibited the best inhibitory activities against 5-HT2AR and MAO-A. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells and normal hepatocytes. I 14 also significantly ameliorated the depression-like behavior of zebrafish and mice. Further study revealed that I 14 was able to occupy the active cavity of 5-HT2AR and MAO-A with multiple hydrogen bonding forces and π–π stacking interaction. I 14 was also able to repair the damage of mice hippocampal neuronal cells and reduce the expression of 5-HT2AR in mice brain tissue. In conclusion, I 14 could be a potential antidepressant candidate for further study.

Discovery of a Novel ASM Direct Inhibitor with a 1,5-Diphenyl-pyrazole Scaffold and Its Antidepressant Mechanism of Action

“…A large number of ethological and neurobiological studies have demonstrated that the animal symptoms caused by the CUMS model are similar to those exhibited by human depressed patients. , Due to its good reliability and validity, the CUMS model has become a valuable experimental tool for screening new drugs with antidepressant efficacy. ICR mice were acclimated to the environment for two consecutive weeks and then stimulated by CUMS for 8 weeks.…”

Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants

“…Depression is a prevalent and severe mental health challenge that impacts millions of people globally. It ranks third in global disability, and the WHO expects it to be the top cause by 2030. − The most widely used therapies for depression are based on the monoamine neurotransmitter hypothesis, which assumes that a deficiency of serotonin or norepin­ephrine in the brain leads to the development of depression. − Traditional antidepressants can help some patients overcome depression. However, these drugs have a delayed onset of action, despite quickly altering mono­aminergic transmission.…”

“…1 H NMR (400 MHz, chloroform-d) δ 7.75 (d, J = 8 3. Hz, 2H), 7.45−7.30 (m, 7H), 4.71 (dd, J = 27.7, 11.2 Hz, 1H), 4.37 (dd, J = 15.9, 11.2 Hz, 1H), 3.79 (s, 3H), 2.45 (s, 3H).…”